title: Shikonin extracted from medicinal Chinese herbs exerts anti-inflammatory effect via proteasome inhibition.
abstract: Shikonin, extracted from medicinal Chinese herb (Lithospermum erythrorhizo), was reported to exert anti-inflammatory and anti-cancer effects both in vitro and in vivo. We have found that proteasome was a molecular target of shikonin in tumor cells, but whether shikonin targets macrophage proteasome needs to be investigated. In the current study, we report that shikonin inhibited inflammation in mouse models as efficiently as dexamethasone. Shikonin at 4 μM reduced the Lipopolysaccharides (LPS)-mediated TNFα release in rat primary macrophage cultures, and blocked the translocation of p65-NF-κB from the cytoplasm to the nucleus, associated with decreased proteasomal activity. Consistently, shikonin accumulated IκB-α, an inhibitor of NF-κB, and ubiquitinated proteins in rat primary macrophage cultures, demonstrating that the proteasome is a target of shikonin under inflammatory conditions. Shikonin also induced macrophage cell apoptosis and cell death. These results demonstrate for the first time that proteasome inhibition by shikonin contributes to its anti-inflammatory effect. The novel finding about macrophage proteasome as a target of shikonin suggests that this medicinal compound has great potential to be developed into an anti-inflammatory agent.
authors.affiliation: Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical College, Guangzhou, Guangdong, PR China.
authors.forename: Li
authors.initials: L
authors.lastname: Lu
authors.forename: Aiping
authors.initials: A
authors.lastname: Qin
authors.forename: Hongbiao
authors.initials: H
authors.lastname: Huang
authors.forename: Ping
authors.initials: P
authors.lastname: Zhou
authors.forename: Chuanyin
authors.initials: C
authors.lastname: Zhang
authors.forename: Ningning
authors.initials: N
authors.lastname: Liu
authors.forename: Shujue
authors.initials: S
authors.lastname: Li
authors.forename: Guanmei
authors.initials: G
authors.lastname: Wen
authors.forename: Change
authors.initials: C
authors.lastname: Zhang
authors.forename: Weihua
authors.initials: W
authors.lastname: Dong
authors.forename: Xuejun
authors.initials: X
authors.lastname: Wang
authors.forename: Q Ping
authors.initials: QP
authors.lastname: Dou
authors.forename: Jinbao
authors.initials: J
authors.lastname: Liu
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use; D002199:Capillary Permeability / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D004365:Drugs, Chinese Herbal / Q000302:isolation & purification* / Q000494:pharmacology* / Q000627:therapeutic use; D054644:Ear Auricle / Q000187:drug effects / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy* / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D029684:Lithospermum / Q000737:chemistry; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009285:Naphthoquinones / Q000302:isolation & purification* / Q000494:pharmacology* / Q000627:therapeutic use; D011480:Protease Inhibitors / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use; D061988:Proteasome Inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D004365:Drugs, Chinese Herbal; D016328:NF-kappa B; D009285:Naphthoquinones; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D014409:Tumor Necrosis Factor-alpha; C016101:shikonin